Numerous hormones and tissues interact to control blood glucose levels. The most important factor in this process is traditionally thought to be the hormone insulin. This is because ingestion of glucose triggers insulin secretion from pancreatic ?-cells, which then acts on insulin receptors in the liver, heart, adipose, and other insulin-sensitive tissues to amplify glucose disposal thus maintaining blood glucose within a narrow range. Decades of work have shown that complete or partial loss of insulin disrupts these and other processes resulting in a general inability to control blood glucose levels. This disease is referred to as Type 1 Diabetes (T1D). Unfortunately, T1D is not a rare disease and it is dangerous because it heightens risk for adverse complications including cardiovascular disease, blindness, kidney disease, and mortality. Further exacerbating this problem is that current therapies rely on insulin therapy, which is life-saving, but is often inadequate to manage T1D and may directly worsen certain complications (5). There are consequently many unmet needs in the treatment of T1D. Fortunately, recent work has uncovered a physiological condition in which complete loss of insulin does not cause T1D. Surprisingly, this animal model that lacks glucagon receptors also exhibits a seemingly normal glucose tolerance despite the absence of insulin stimulated effects on liver, skeletal muscle, etc. It is still unclear, however, if this nomal glucose disposal is actually similar to normal, insulin-intact animals or if alternative mechanisms are engaged. It is also unclear what regulatory factor(s) are involved. Aim 1 of this proposal builds upon preliminary data to determine whether glucose disposition in T1D glucagon receptor-null mice is normal or if other routes of disposal are engaged. Preliminary data based on stable and radioactive glucose tracers indicates that insulin-independent gluco-regulatory mechanisms are up-regulated in insulin-deficient (e.g. T1D) glucagon receptor-null mice. Compensatory increases in these other pathways appear to promote glucose metabolism in skeletal muscle to lactate, which is used for indirect glycogen synthesis in the liver. Aim 2 of ths proposal is to determine whether fibroblast growth factors (FGFs), particular FGF21, are needed for insulin-deficient glucagon receptor null mice to maintain normal blood glucose levels and glucose tolerance. This will be done using a two genetically modified mouse models in which either the co-receptor required for FGF signaling, ?-klotho, or FGF21 is deleted on a glucagon receptor-null background. Aim 3 builds upon the notion that indirect glycogen synthesis is up-regulated in insulin-deficient glucagon receptor-null mice. This process will be nullified by deleting phosphenolpyruvate kinase (PEPCK) specifically in the liver on a glucagon-receptor null background. PEPCK is a critical enzyme in the liver needed for glycogen synthesis thus its absence should abolish the protective phenotype if the hypothesis is accurate. Completing these aims will provide a better understanding of how this unique model is protected from T1D and offer insight regarding the tractability of these processes as drug targets.